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FR171456 is a specific inhibitor of mammalian NSDHL and yeast Erg26p.
- Source :
-
Nature communications [Nat Commun] 2015 Oct 12; Vol. 6, pp. 8613. Date of Electronic Publication: 2015 Oct 12. - Publication Year :
- 2015
-
Abstract
- FR171456 is a natural product with cholesterol-lowering properties in animal models, but its molecular target is unknown, which hinders further drug development. Here we show that FR171456 specifically targets the sterol-4-alpha-carboxylate-3-dehydrogenase (Saccharomyces cerevisiae--Erg26p, Homo sapiens--NSDHL (NAD(P) dependent steroid dehydrogenase-like)), an essential enzyme in the ergosterol/cholesterol biosynthesis pathway. FR171456 significantly alters the levels of cholesterol pathway intermediates in human and yeast cells. Genome-wide yeast haploinsufficiency profiling experiments highlight the erg26/ERG26 strain, and multiple mutations in ERG26 confer resistance to FR171456 in growth and enzyme assays. Some of these ERG26 mutations likely alter Erg26 binding to FR171456, based on a model of Erg26. Finally, we show that FR171456 inhibits an artificial Hepatitis C viral replicon, and has broad antifungal activity, suggesting potential additional utility as an anti-infective. The discovery of the target and binding site of FR171456 within the target will aid further development of this compound.
- Subjects :
- 3-Hydroxysteroid Dehydrogenases genetics
Candida albicans
Cholesterol chemistry
Drug Resistance, Fungal genetics
Ergosterol biosynthesis
Mutation
Saccharomyces cerevisiae Proteins genetics
3-Hydroxysteroid Dehydrogenases antagonists & inhibitors
Antifungal Agents chemistry
Cholesterol analogs & derivatives
Saccharomyces cerevisiae genetics
Saccharomyces cerevisiae Proteins antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 6
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 26456460
- Full Text :
- https://doi.org/10.1038/ncomms9613